Project Summary Of the multiple classes of functional elements encoded in the genome, non-coding RNA genes and regulatory elements are some of the least functionally characterized in terms of their specific contributions to the whole organism. While great strides have been made in identifying these elements at the biochemical level, there is still much work to be done. Parsing them into specific functions will greatly enable the biomedical community to use them to accurately diagnose genetic lesions and to treat human disease. This project develops and applies novel computational tools to assign specific biological functions to genes and regulatory elements based on their patterns of evolution among more than 60 mammalian species. The tools will also be applicable to other model taxonomic groups with sequenced genomes, such as insects, nematodes, plants, and fungi. The resulting functional assignments will be invaluable to focus and prioritize experimental efforts and will reveal the pathogenic effects of genetic mutations in patients. The project specifically develops and distributes programs to analyze organismal traits (phenotypes) that show variation over evolutionary time. By exploiting their variation within a large number of species, these programs identify those specific genetic elements whose rates of evolution are associated with the trait. The first aim provides computational tools and algorithms to study continuous trait variables, and applies them to identify genes accommodating long lifespan in mammals. The second aim delivers a computational toolset to determine the functions of regulatory regions and non-coding RNA genes, with specific applications to eye and ear development. The resulting set of enhancers and promoters will be highly valuable for the identification of important mutations in non-coding sequences of hearing- and vision-compromised patients. The final aim distributes these programs to the public as code and through a user-friendly web-based interface. Any biomedical researcher will be able to upload their trait/phenotype of interest across mammalian species and rapidly retrieve genes and regulatory regions associated with their trait along with vital statistical measures and tools for downstream analysis and visualization. To provide access to human and model organism genes, the user will have access to pre-computed genome-wide datasets in mammals, insects, nematodes, and fungi. The culmination of this research program will enable the rapid identification of genes and regulatory elements underlying countless morphological and physiological traits, thereby propelling experimental and medical genetics research with the power of evolutionary biology.